The functional role of midbrain dopamine (DA) neurons in motivating and reinforcing behaviors is supported by a wealth of data, leading to a well described route by which drugs of abuse cause addiction. In this work, a single function is commonly supposed for all DA neurons in signaling errors in reward prediction. This supposition has been challenged by recent findings that previously unrecognized sub-population of DA neurons in the medial posterior VTA respond to aversive and not rewarding stimuli. These findings have been replicated in three species across three independent laboratories. In addition to differentiation on the basis of reward and punishment, this population of DA neurons also project to different target regions than the rest of the DA system. In this project, we aim to identify a parallel differentiation of function and anatomy in the human midbrain using brainstem functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI).fMRI has been used profitably in the study of reward in recent years. Investigation of responses within the VTA and SN has required methodological advances recently developed by the PI and collaborators. Recent preliminary work indicates that we are able to differentiate functionally distinct sub-regions within the VTA/SN indicating feasibility of using fMRI in the current project. Additionally, preliminary work described in the proposal indicates that we are able to perform white matter fiber tracking from midbrain seed regions in the VTA/SN to areas in the striatum. Proposed studies combine these methods to identify parallel systems in the human DAergic midbrain.The potential consequences of functionally distinct populations of DA neurons are profound for research into addiction. Drugs of abuse enhance DA throughout the brain; a complete understanding of behavioral consequences of drug ingestion requires understanding the function of DA in all target regions. Animal research is excellent for precisely identifying sub-populations of DA neurons. However, identification of similar systems in humans is necessary to link animal work to behaviors relevant for addiction. PUBLIC HEALTH RELEVANCE: A significant departure is underway regarding theories of dopamine function in the brain and this has profound consequences for understanding drug addiction. We extend methods developed for imaging from the human midbrain and develop novel tools for white matter fiber tracking to identify functional sub-regions within human VTA/SN. These methods are crucial for extending recent findings from animal research to human behaviors relevant to addiction.